Cinacalcet (I) belongs to a class of calcimimetic agents which decrease the secretion of parathyroid hormone (“PTH”) by activating calcium receptors.

Cinacalcet may be named as (R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-napthyl)ethylamine.
Cinacalcet hydrochloride, marketed as SENSIPAR™, is used to treat hyperparathyroidism. Calcimimetic agents increase the sensitivity of calcium receptor to calcium, which inhibits the release of parathyroid hormone and lowers parathyroid hormone levels within a short time.
U.S. Pat. No. 6,011,068 discloses inorganic ion receptors, specifically calcium receptors.
U.S. Pat. No. 6,211,244 specifically discloses cinacalcet, its pharmaceutically acceptable salt or complex and a process for the preparation of it. However, the process disclosed in U.S. Pat. No. 6,211,244 involves the use of flammable and toxic reagents such as titanium isopropoxide, ethanolic or methanolic cyanoborohydride.
It is observed that cinacalcet obtained by the prior art process is not absolutely pure. It may contain traces of starting material, solvent contaminations, side products and byproducts generated during the reaction. Such impurities result in a decrease in the purity of the final product, hence they are undesirable.
X. Wang et. al, Tetrahedron Letters 45 (2004) 8355-8358, teach that they have identified two new isomeric dihydronaphthalene impurities.
The inventors of US20070060645 have identified an impurity generated during the synthesis of cinacalcet and designated it as cinacalcet carbamate impurity. US20070060645 further describes a HPLC method to detect the carbamate impurity. However, it does not provide any method of minimizing the carbamate impurity.
WO2008058236 describes a desfluoro impurity generated during the synthesis of cinacalcet that can be detected at a relative retention time (RRT) of 0.9 during HPLC analysis.
All the impurities described in the above prior art references are undesirable and need to be removed so as to obtain a higher purity final product. Hence, there is a need to develop a process for the preparation of cinacalcet that is simple, avoids generation of impurities, is easy to scale up and involves the use of reagents that are readily available and safe to handle.
(R)-1-naphthylethylamine is a key intermediate in the synthesis of cinacalcet and its salts. It can be obtained by resolution of racemic 1-naphthylethylamine. U.S. Pat. No. 2,996,545 describes a method of resolution of 1-naphthylethylamine using d-tartaric acid in the presence of methanol to obtain the corresponding tartrate salt. The tartrate salt is purified by fractional crystallization to obtain crystalline optically pure (R)-1-naphthylethylamine. The crystallization steps need to be repeated a number of times until a constant optical rotation and the desired optical purity is obtained. Repeated crystallizations are difficult to carry out industrially and result in material loss. Also, the (R)-1-naphthylethylamine is obtained as an oily residue which needs to be further isolated by distillation. This affects the final yield of the product.
U.S. Pat. No. 2,996,545 further describes that L-malic acid and D-camphoric acid have been used for resolution of racemic amines. Both these optically active acids are expensive. It further states that L-malic acid is found unsatisfactory particularly for resolution of naphthylethylamine as it is expensive, its recovery for re-use is difficult and losses of material are high. Further, the purification of amine malate salt is tedious, expensive and never complete which results in partially resolved amines.
JP58024545 discloses the use of cis-2-benzamidocyclohexane carboxylic acid as a resolving agent for resolution of 1-naphthylethylamine.
There has been no disclosure of a simple and industrially-suitable method for resolution of 1-naphthylethylamine. The present invention provides a process for the resolution of 1-naphthylethylamine and also describes a new method of synthesis of cinacalcet and salts thereof.